title: Strain-dependent genomic factors affect allergen-induced airway hyperresponsiveness in mice.
abstract: Asthma is etiologically and clinically heterogeneous, making the genomic basis of asthma difficult to identify. We exploited the strain-dependence of a murine model of allergic airway disease to identify different genomic responses in the lung. BALB/cJ and C57BL/6J mice were sensitized with the immunodominant allergen from the Dermatophagoides pteronyssinus species of house dust mite (Der p 1), without exogenous adjuvant, and the mice then underwent a single challenge with Der p 1. Allergic inflammation, serum antibody titers, mucous metaplasia, and airway hyperresponsiveness were evaluated 72 hours after airway challenge. Whole-lung gene expression analyses were conducted to identify genomic responses to allergen challenge. Der p 1-challenged BALB/cJ mice produced all the key features of allergic airway disease. In comparison, C57BL/6J mice produced exaggerated Th2-biased responses and inflammation, but exhibited an unexpected decrease in airway hyperresponsiveness compared with control mice. Lung gene expression analysis revealed genes that were shared by both strains and a set of down-regulated genes unique to C57BL/6J mice, including several G-protein-coupled receptors involved in airway smooth muscle contraction, most notably the M2 muscarinic receptor, which we show is expressed in airway smooth muscle and was decreased at the protein level after challenge with Der p 1. Murine strain-dependent genomic responses in the lung offer insights into the different biological pathways that develop after allergen challenge. This study of two different murine strains demonstrates that inflammation and airway hyperresponsiveness can be decoupled, and suggests that the down-modulation of expression of G-protein-coupled receptors involved in regulating airway smooth muscle contraction may contribute to this dissociation.
authors.affiliation: Molecular Genetics Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-0148, USA.
authors.forename: Samir N P
authors.initials: SN
authors.lastname: Kelada
authors.forename: Mark S
authors.initials: MS
authors.lastname: Wilson
authors.forename: Urraca
authors.initials: U
authors.lastname: Tavarez
authors.forename: Kari
authors.initials: K
authors.lastname: Kubalanza
authors.forename: Bhavesh
authors.initials: B
authors.lastname: Borate
authors.forename: Greg S
authors.initials: GS
authors.lastname: Whitehead
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Maruoka
authors.forename: Michelle G
authors.initials: MG
authors.lastname: Roy
authors.forename: Michelle
authors.initials: M
authors.lastname: Olive
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Carpenter
authors.forename: David M
authors.initials: DM
authors.lastname: Brass
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.forename: Donald N
authors.initials: DN
authors.lastname: Cook
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Evans
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
mesh_terms: D000403:Airway Resistance / Q000235:genetics; D000485:Allergens; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology*; D060829:Arthropod Proteins; D001249:Asthma / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects / Q000235:genetics*; D016085:Bronchoconstrictor Agents; D003546:Cysteine Endopeptidases; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D008168:Lung / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009077:Mucins / Q000378:metabolism; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D018418:Th2 Cells / Q000276:immunology; D013997:Time Factors
chemical_list: D000485:Allergens; D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; D016085:Bronchoconstrictor Agents; D016207:Cytokines; D007074:Immunoglobulin G; D009077:Mucins; D043562:Receptors, G-Protein-Coupled; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D003546:Cysteine Endopeptidases; C451162:Dermatophagoides pteronyssinus antigen p 1